DESCRIPTION: The overall objectives of this proposal are to evaluate the role of the nervous system [i.e., cholinergic, adrenergic, and dopaminergic innervation], hormones (i.e., gastrin), and toxic agents [carbon tetrachloride (CCl4)] in the regulation of secretion, growth, and apoptosis of distinct subpopulations of small and large cholangiocytes or intrahepatic bile duct units (IBDU) from normal and bile duct ligated (BDL) rats. This hypothesis is based upon our previous studies and preliminary data showing that: (i) the cholinergic, adrenergic, and dopaminergic system, and the hormone gastrin modifies cholangiocyte growth and secretion through up- or down-regulation of the Ca2+-dependent PKC system; and (ii) CCl4-induced damage of large hormone-responsive ducts is regulated by the PKC system. To evaluate our hypothesis, three specific aims are proposed : (i) to test the hypothesis that cholinergic, adrenergic, and dopaminergic innervation regulates cholangiocyte growth, and secretion of different sized ducts; (ii) to test the hypothesis that gastrin decreases growth in hyperplastic rat cholangiocytes and in cholangiocarcinoma cell lines through activation and cytoskeleton to membrane translocadon of Ca2+-dependent PKC alpha; and (iii) to test the hypothesis that CCl4-induced duct injury response consisting of cholangiocyte apoptosis followed by cholangiocyte proliferation is dependent on the PKC pathway. In BDL rats, proliferative and secretory processes of small and large cholangiocytes originating from small and large ducts, respectively will be evaluated. Furthermore, small and large IBDU will also be employed to confirm that our observations in different sizes of cholangiocytes is also present in the corresponding sized ducts. These studies will evaluate both in vivo and in vitro the differential proliferative, and secretory responses of small and large cholangiocytes or IBDU to specific cholinergic, adrenergic, and dopaminergic agonists/antagonists, gastrin, or CCl4 treatment. The results should provide new insight into the mechanisms of cholangiocyte growth, and secretion of different sized ducts.